ES2256276T3 - LACTIC ACID POLYMER AND PROCEDURE FOR PRODUCTION. - Google Patents

Abstract

A pharmaceutical preparation, e.g. a sustained-release microcapsule preparation, comprising a lactic acid polymer of 15,000 to 50,000 in weight-average molecular weight, the content of polymeric materials having not more than about 5,000 in weight-average molecular weight therein being not more than about 5% by weight. The sustained-released microcapsule preparation encapsulating a physiologically active substance can fully prevent the initial excessive release of the physiologically active substance from the microcapsules and keep a stable release rate over a long period of time.

Description

Lactic acid polymer and procedure for its production.

Technical field

The present invention relates to a polymer biodegradable useful as a matrix for preparations Pharmaceuticals

Prior art

Biodegradable polymers that have a Sustained release property are useful as matrices for microcapsules, etc. to be used to encapsulate substances Physiologically active How these biodegradable polymers are known, for example, poly (lactic acid) and an acid copolymer lactic acid and glycolic acid (for example, document JP-A-11/269094).

These biodegradable polymers are useful when They are produced by conventional synthetic procedures. However, it has been found that these polymers produced by ring opening polymerization they have a content small of terminal carboxyl groups and have a utilization sparse as sustained release matrices. For this reason, it have made attempts to submit biodegradable polymers by weight molecular elevated to hydrolysis to make its molecular weights weight means are adequate and can then be used as a matrix for sustained release preparations. Polymers obtained by hydrolysis and subsequent washing with water, without However, they are apt to cause an initial abrupt detachment and, therefore, are not suitable for release matrices sustained, even when said polymers have molecular weights appropriate weight media and contents of carboxyl groups terminals Therefore, an additional improvement is required.

Description of the invention Technical problem (s) to be solved (s) by means of the invention

Under the above circumstances, this invention has been prepared with the aim of providing a lactic acid polymer useful for release preparations sustained that can completely prevent the initial release excessive (initial abrupt detachment) of a substance physiologically active from the microcapsules that encapsulate a physiologically active substance and maintain a physiologically stable substance release rate active for a long period of time (solution of technical problems)).

As a result of the extensive study, it has found that a lactic acid polymer obtained by hydrolysis, that is, a lactic acid polymer that has a decreased content of low weight polymeric materials molecular, particularly having a molecular weight of no more of 5,000, it is difficult to cause the initial abrupt detachment and is suitable as a matrix for release preparations sustained. Based on this discovery, the present invention

According to the present invention, a procedure to produce a lactic acid polymer with a weight average molecular weight of 15,000 to 50,000, in which the content of polymeric materials with an average molecular weight weight of no more than approximately 5,000 is no more than approximately 5% by weight, which comprises hydrolyzing a polymer of high molecular weight lactic acid, contact the resulting solution containing the hydrolyzed product with a solvent selected from a group consisting of alcohols, acyclic ethers and aliphatic hydrocarbons, and separate and collect the precipitated lactic acid polymer.

A polymer of additionally is provided lactic acid with a weight average molecular weight of 15,000 to 50,000, in which the content of polymeric materials with a weight molecular weight average of no more than 5,000 is no more than approximately 5% by weight.

The use of the polymer is also provided of lactic acid as previously established as a matrix for sustained release preparations and a matrix for sustained release preparations comprising the polymer of lactic acid as stated above.

Enhanced effect compared to technique previous

In comparison with lactic acid polymers conventional used as biodegradable polymers for sustained release preparations, lactic acid polymer of this invention has a smaller content of materials low molecular weight polymers, particularly having a weight molecular weight average of no more than 5,000 and, therefore, barely causes excessive initial release.

Best way to practice the invention

The lactic acid polymer of this invention may comprise a homopolymer of lactic acid or a copolymer of lactic acid with any other monomer (for example, acid glycolic). This homopolymer or copolymer usually has a content of polymeric materials having an average molecular weight weight of no more than 5,000 of no more than about 5% by weight, preferably a content of polymeric materials that they have a weight average molecular weight of no more than 5,000 which is of no more than about 5% by weight, with a content of polymeric materials having a weight average molecular weight of no more than 3,000 which is no more than about 1.5% by weight, more preferably a content of polymeric materials that have a weight average molecular weight of no more than 5,000 which is no more of approximately 5% by weight, with a content of materials polymers having a weight average molecular weight of no more than 3,000 which is no more than about 1.5% by weight and a content of polymeric materials that have a molecular weight weight average of no more than 1,000 which is of or more than approximately 0.1% by weight.

The lactic acid polymer of the present invention usually has a weight average molecular weight of 15,000 to 50,000, preferably 15,000 to 30,000, more preferably 20,000 to 25,000.

The molecular weight lactic acid polymer high that will be used as starting material for the preparation of the lactic acid polymer object of the invention it can be commercially available or it can be obtained by polymerization in a conventional manner and usually has a weight average molecular weight of 15,000 to 50,000, preferably 30,000 to 100,000. Conventional polymerization methods include polycondensation of lactic acid, if necessary, with glycolic acid, ring opening polymerization lactide, if necessary, with glycolide in the presence of a catalyst as a Lewis acid (for example, diethyl zinc, triethyl aluminum or stannous octanoate) or a metal salt, polymerization with opening of the lactide ring in the same way as above, except for the presence of a derivative of hydroxycarboxylic acid in which the carboxyl group is protected (for example, see International Publication No. WO 00/35990), polymerization with lactide ring opening using a catalyst under heating (for example, see J. Med. Chem., 16, 897 (1973)), copolymerization of lactide with glycolide, etc.

As the polymerization mode, there is a mass polymerization in which the lactide or the like is subjected to polymerization in the form of a molten product, polymerization in solution in which the lactide or the like is subjected to polymerization in the form of a solution in an appropriate solvent, etc. In this invention, is favorable from the point of view of production industrial use a molecular weight lactic acid polymer raised by solution polymerization as the material of heading for the production of lactic acid polymer objective.

The solvent to be used in the Solution polymerization to dissolve the lactide can be, by for example, aromatic hydrocarbons (for example, benzene, toluene or xylene), decalin, dimethylformamide or the like.

In order to hydrolyze the acid polymer High molecular weight lactic acid thus obtained, can be adopted a conventional hydrolyzing process by itself. By For example, the high molecular weight lactic acid polymer is dissolved in an appropriate solvent and added to the same water and, if an acid is necessary, followed by the reaction.

The solvent that dissolves the acid polymer High molecular weight lactic acid can be any one capable of dissolve one part by weight of said polymer in no more than 10 parts in weigh. Specific examples are halogenated hydrocarbons (for for example, chloroform or dichloromethane), aromatic hydrocarbons (for example, toluene, o-xylene, m-xylene or p-xylene), cyclic ethers (for example, tetrahydrofuran), acetone, N, N-dimethylformamide, etc. When the solvent used in the polymerization for the production of high molecular weight lactic acid polymer It is one that is also unstable for the hydrolysis of this polymer,  polymerization and hydrolysis can be carried out successively without insulating the lactic acid polymer by weight high molecular polymerized.

The amount of solvent that dissolves the high molecular weight lactic acid polymer is usually 0.1 to 100 times by weight, preferably 1 to 10 times by weight of said polymer in the form of the solute. The amount of water which will be added is usually 0.001 to 1 part by weight, preferably 0.01 to 0.1 part by weight to a part by weight of the high molecular weight lactic acid polymer.

Examples of the acid that can be added when if necessary include inorganic acids (for example, acid hydrochloric, sulfuric acid or nitric acid), organic acids (by example, lactic acid, acetic acid or trifluroacetic acid), etc., among which lactic acid is preferred. The amount of the acid to be added is usually no more than 10 parts by weight, preferably 0.1 to 1 part by weight for a part by weight of molecular weight lactic acid polymer high.

The reaction temperature for hydrolysis it is usually 0 to 150 ° C, preferably 20 to 80 ° C. The time of reaction for hydrolysis varies with the average molecular weight weight of the high molecular weight lactic acid polymer and the reaction time is usually 10 minutes to 100 hours, preferably 1 to 20 hours.

The completeness of the hydrolysis can be determined based on the weight average molecular weight of the hydrolyzed product Namely, product sampling Hydrolyzate is done at a suitable interval during hydrolysis, and the weight average molecular weight of the hydrolyzed product of which samples are taken is measured by gel permeation chromatography (CPG). When it is confirmed that the weight average molecular weight is approximately 15,000 to 50,000, preferably approximately 15,000 to 30,000, more preferably about 20,000 to 25,000, the hydrolysis is finished.

The method to precipitate the acid polymer target lactic from the solution that contains the product hydrolyzate obtained by hydrolyzing the lactic acid polymer of high molecular weight includes, for example, a method of putting in contact a solution containing the hydrolyzed product with a solvent capable of precipitating the lactic acid polymer objective in it.

The solution that contains the hydrolyzed product it is preferred to one in which the weight lactic acid polymer molecular weight average of 15,000 to 50,000, preferably 15,000 at 30,000, more preferably 20,000 to 25,000 is dissolved in a solvent such as halogenated hydrocarbons (for example, chloroform or dichloromethane), aromatic hydrocarbons (for example, toluene, o-xylene, m-xylene or p-xylene), cyclic ethers (for example, tetrahydrofuran), acetone or N, N-dimethylformamide a a concentration of about 10 to 50% by weight.

The solvent to precipitate the polymer from target lactic acid in the solution that contains the product hydrolyzate can be, for example, alcohols (for example, methanol or ethanol), acyclic ethers (for example, isopropyl ether), aliphatic hydrocarbons (for example, hexane), water or Similar.

The amount of solvent capable of precipitating the target lactic acid polymer is usually 0.1 to 100 parts by weight, preferably 1 to 10 parts by weight for one part by weight of the liquid medium in the solution containing the product hydrolyzed

A preferred example of the combination of the medium liquid and solvent as well as its proportions is the combination using 2 to 10 parts by weight of isopropyl ether as the solvent to reduce the solubility of the target lactic acid polymer to a part by weight of dichloromethane, which is used as the medium liquid in the solution containing the hydrolyzed product in a 1 to 5 part ratio for one part by weight of the solute.

After contact of the solvent capable of precipitate the target lactic acid polymer with the solution containing the hydrolyzed product, the temperature of said Solvent is usually -20 to 60 ° C, preferably 0 to 40 ° C, and the temperature of said solution is usually 0 to 40 ° C, preferably 10 to 30 ° C.

As the procedure to contact the solvent capable of precipitating the target lactic acid with the solution containing the hydrolyzed product, is the addition of said solution to said solvent at once, the dropwise addition to drop of said solution to said solvent, adding said solvent to said solution at once, the dropwise addition of said solvent to said solution, etc.

The lactic acid polymer of the invention as well obtained has a favorable content of carboxyl groups terminals suitable for a matrix for release preparations sustained and can be used as such matrix. When the polymer of lactic acid is used as a matrix for preparations of sustained release, a physiologically active substance that goes to be encapsulated therein has no limitations Particularly insofar as it is pharmacologically effective. The substance physiologically active may be a peptide compound or a non-peptide compound. As the non-peptide compound, they are like examples an agonist, an antagonist, a compound that has a enzymatic inhibition activity, etc.

A peptide compound is preferred, for example, that is a physiologically active one, especially that it has a molecular weight of about 300 to 40,000, preferably of approximately 400 to 30,000, more preferably of approximately 500 to 25,000, most preferably of approximately 500 to 20,000.

Examples of the physiologically active peptide include luteinizing hormone release hormone (LH-RH), insulin, somatostatin, hormone growth, growth hormone release hormone (GH-RH), prolactin, erythropoietin, hormone adrenocortical, melanocyte stimulation hormone, hormone Thyroid hormone release, thyroid stimulating hormone, luteinizing hormone, follicle stimulating hormone, vasopressin, oxytocin, calcitonin, gastrin, secretin, pancreozimine, cholecystokinin, angiotensin, lactogen human placental, human choriogonadotropin, encephalin, endorphin, kiotorphine, tuftsin, thympoietin, thymosin, Thymotimulin, thymus tumor factor, blood thymic factor, tumor necrosis factor, colony inducing factor, motilin, dinorphine, bombesin, neurotensin, cerulein, bradykinin, factor atrial natriuretic nerve growth factor cell proliferation, neurotrophic factor, peptide antagonist of endothelin, etc., its derivatives, its fragments and its derivatives, etc.

The physiologically active peptide may be in a free form or a pharmacologically acceptable salt form. Examples of the salt are, in the case of the physiologically peptide active that has a basic group like amino, salts with acids inorganic (for example, carbonic acid, bicarbonic acid, acid hydrochloric, sulfuric acid, nitric acid or boric acid), salts with organic acid (for example, succinic acid, acetic acid, propionic acid, trifluoroacetic acid), etc. In the case of physiologically active peptide having an acidic group such as carboxyl, example of the salt are salts with inorganic bases as alkali metals (for example, sodium or potassium) and metals alkaline earth (for example, calcium or magnesium), salts with organic bases such as organic amines (for example, triethylamine) and basic amino acids (for example, arginine). He physiologically active peptide can also form a complex metallic as a copper complex or a zinc complex.

Among the physiologically active peptides previously illustrated, derivatives of LH-RH and its salts that are effective in treatment of sex hormone dependent diseases such as cancer of prostate, benign prostatic hyperplasia, endometriosis, fibroid, precocious puberty and breast cancer or may be useful for contraception. Specific examples are leuprorelin, buserelin, goserelin, triptorelin, napharelin, histrelin, deslorelin, meterelin, gonadorelin, etc.

The sustained release preparation prepared by using the lactic acid polymer of the invention as matrix may contain, in addition to the physiologically substance active, a surfactant like Tween 80 (manufactured by the company Atlas Powder) and HCO-60 (manufactured by Nikko Chemicals), a polysaccharide such as carboxymethyl cellulose, alginate sodium and sodium hyaluronate, a dispersant such as sulfate protamine and polyethylene glycol 400, a preservative such as methylparaben and propylparaben, an isotonic agent such as sodium chloride, mannitol, sorbitol and glucose, an oil or fat such as sesame oil and corn oil, a phospholipid like lecithin, an excipient like lactose, corn starch, mannitol and cellulose, a binding agent to dextrin such as sucrose, gum arabic, methylcellulose and carboxymethyl cellulose, a disintegrant such as carboxymethyl cellulose of calcium, a drug retention agent such as gelatin, acid hydroxynaphthoic and salicylic acid, etc.

The sustained release preparation that comprises the lactic acid polymer of the invention as the biodegradable polymer can be repaired by a method conventional by itself as an underwater drying method, a phase separation method, a spray drying method or Any other analogous method.

The preparation of microcapsules (called sometimes "microspheres") as an example of the preparation of Sustained release will be explained below. At any stage or phase in the preparation method, any retention agent of drugs (for example, gelatin, hiroxinaphthoic acid or salicylic acid) can be optionally used in a conventional way by itself same.

(I) Water drying method (i) O / W method

In this method, a first lactic acid polymer solution of the present invention (sometimes referred to as "biodegradable polymer") in an organic solvent. The organic solvent usable for preparation of a sustained release preparation according to the invention is preferred to have a boiling point of 120 ° C or lower.

As the organic solvent, they can be used, for eg halogenated hydrocarbons (for example, dichloromethane, chloroform, dichloroethane, trichloroethane, carbon tetrachloride), ethers (for example, ethyl ether, isopropyl ether), acid esters fatty (for example, ethyl acetate, butyl acetate), aromatic hydrocarbons (for example, benzene, toluene, xylene), alcohols (eg, ethanol, methanol), acetonitrile, etc. Between The use of halogenated hydrocarbons is favorable, particularly dichloromethane. These solvents can be used in a mixture in an appropriate proportion, and in this case, they are preferred mixtures of halogenated hydrocarbons and alcohols, particularly a mixture of dichloromethane and ethanol.

The concentration of the biodegradable polymer of the invention in the solution is varied with the molecular weight of the Biodegradable polymer and the type of organic solvent. By example, when dichloromethane is used as the organic solvent, the concentration can usually be about 0.5 to 70% by weight, preferably about 1 to 60% by weight, more preferably about 2 to 50% by weight. If that a mixture of dichloromethane and ethanol be used as the organic solvent, ethanol can generally be used in a amount of about 0.01 to 50% (v / v), preferably of approximately 0.05 to 40% (v / v), more preferably of approximately 0.1 to 30% (v / v) based on the total amount of they.

To the organic solution thus prepared from the polymer biodegradable, a physiologically active substance is added to dissolve or disperse. The physiologically active substance is used in an amount such that the weight ratio of the substance physiologically active and the biodegradable polymer is not usually more than about 1/1, preferably not more than about 1/2.

Then the organic solution that includes the physiologically active substance or its salt and the polymer biodegradable are added to an aqueous phase to prepare a O emulsion (oily phase) / W (aqueous phase), followed of evaporation of the solvent in the oily phase to Provide microcapsules The volume of the aqueous phase is usually about 1 to 10,000 times, preferably 5 to 50,000 times, more preferably about 10 to 2,000 times that of the oily phase.

When desired, a emulsifier in the aqueous phase. In general, the emulsifier can be anyone capable of forming a stable O / W emulsion. Examples Specific emulsifier usable are anionic surfactants (for example, sodium oleate, sodium stearate, sodium lauryl sulfate), non-ionic surfactants (for example, fatty acid esters of polyoxyethylene sorbitan [Tween 80, Tween 60, manufactured by the company Atlas Powder], derived from polyoxyethylene-castor oil [HCO-60, HCO-50, manufactured by the Nikko Chemicals]), polyvinylpyrrolidone, poly (alcohol vinyl), carboxymethyl cellulose, lecithin, gelatin, hyaluronic acid, etc. These emulsifiers can be used alone or in combination. When used, the concentration of the emulsifier it is preferred that it be about 0.01 to 10% in weight, particularly about 0.05 to 5% by weight.

A regulatory agent may also be incorporated. of the osmotic pressure in the aqueous phase. As the regulatory agent of osmotic pressure, anyone capable of displaying an osmotic pressure in aqueous solution. As the regulatory agent of osmotic pressure, polyvalent alcohols are illustrative,  monovalent alcohols, monosaccharides, disaccharides, oligosaccharides and amino acids, and their derivatives.

Examples of polyvalent alcohols are trivalent alcohols (eg glycerol), alcohols pentavalent (for example, arabitol, xylitol, adonitol), alcohols hexavalent (for example, mannitol, sorbitol, dulcitol), etc. From these, the use of hexavalent alcohols is preferred, particularly mannitol Examples of monovalent alcohols are methanol, ethanol, isopropanol, etc., among which it is preferable ethanol. Examples of monosaccharides are pentoses (for example, arabinose, xylose, ribose, 2-deoxyribose), hexoses  (for example, glucose, fructose, galactose, mannose, sorbose, rhamnose, fucose), etc., among which the use of hexoses How oligosaccharides can be used, for example, trisaccharides (for example matotriose or raffinose), tetrasaccharides (eg stachy) of those who are favorably used trisaccharides

Derivatives of monosaccharides, disaccharides and oligosaccharides include, for example, glucosamine, galactosamine, glucuronic acid, galacturonic acid, etc. Amino acids are Usable to the extent that they are L configuration, and the Specific examples are glycine, leucine, arginine, etc. of those who L-arginine is preferred.

Said osmotic pressure regulating agents They can be used alone or in combination. When used, the concentration may be such that it results in osmotic pressure of the aqueous phase is approximately 1/5 to 5 times, preferably 1/25 to 3 times that of saline solution physiological

The organic solvent separation can be performed by a conventional procedure by itself or any other procedure similar to it. For example, the evaporation of the organic solvent is carried out under pressure atmospheric or gradually reduced pressure, while stirring with a propeller type stirrer or a magnetic stirrer or under the vacuum degree control by using an evaporator Rotary

The microcapsules thus prepared are collected by centrifugation or filtration, they are washed with distilled water repeatedly to remove the substance physiologically active, the emulsifier and any other material adhered to the microcapsule surfaces and turned to disperse in distilled water, followed by lyophilization.

During processing, a anti-cohesion agent for microcapsules for prevention of cohesion between them. Agent Examples anti-cohesion are water soluble polysaccharides (for example, mannitol, lactose, glucose, starches such as starch corn), amino acids (for example, glycine), proteins (for example, fibrin or collagen), etc. Among them, mannitol is preferred.

After lyophilization, moisture and organic solvent in the microcapsules can be optionally removed by heating under a condition that does not cause the microemulsions to melt. Heating is preferably carried out at a temperature slightly higher than the glass transition temperature of the mid-point of the biodegradable polymer, as determined by the use of a differential scanning calorimeter under a temperature rise rate of 10 to 20 ° C / min. More preferably, the heating is carried out at a temperature from the glass transition temperature midpoint of the biodegradable polymer to about 3 ° C higher than the temperature of said glass transition temperature midpoint. In the case where a lactic acid / glycolic acid copolymer is used as the biodegradable polymer, it is particularly preferred to heat at a temperature between the mid-point glass transition temperature of said copolymer and 10 ° C above this glass transition temperature of midpoint, more preferably between said glass transition temperature midpoint and 5 ° C higher than this glass transition temperature point
means, medium.

The heating time is varied with the amount of the microcapsules and is usually about 12 to 168 hours, preferably approximately 24 to 120 hours, more preferably about 48 to 96 hours after the microcapsules themselves reach a temperature default

Any particular restrictions are present in the heating procedure to the extent that the collection of the microcapsules are uniformly heated. Therefore, it carries out this heating, for example, by drying with heat in a thermostated bath, a fluidized bed reservoir, a mobile bath or a boiler or drying with heat by microwave. Especially, heating drying in a bath is preferable thermostated

(ii) W / O / W method

In this method, a first solution of the biodegradable polymer of the invention in a organic solvent

As the organic solvent can be used, for example, halogenated hydrocarbons (for example, dichloromethane, chloroform, dichloroethane, trichloroethane, carbon tetrachloride), ethers (for example, ethyl ether, isopropyl ether), acid esters fatty (for example, ethyl acetate, butyl acetate), aromatic hydrocarbons (for example, benzene, toluene, xylene), alcohols (eg, ethanol, methanol), acetonitrile, etc. Between they are favorable in the use of halogenated hydrocarbons, particularly dichloromethane. These solvents can be used in a mixture in an appropriate proportion, and in this case they are preferred mixtures of halogenated hydrocarbons and alcohols, particularly a mixture of dichloromethane and ethanol.

The concentration of the biodegradable polymer in the Organic solution is varied with the molecular weight of the polymer Biodegradable and the type of organic solvent. For example when dichloromethane is used as the organic solvent, the concentration it can usually be approximately 0.5 to 70% by weight, preferably about 1 to 60% by weight, more preferably about 2 to 50% by weight.

To the organic solution thus prepared from the polymer biodegradable (oily phase) a solution of a physiologically active substance or its salt (using water or a mixture of water and an alcohol (for example, methanol or ethanol) as solvent The resulting mixture is emulsified by a conventional procedure by itself with a homogenizer or ultrasonic means to form a W / O emulsion.

Then the W / O emulsion thus obtained, which comprises the physiologically active substance and the polymer Biodegradable is added to an aqueous phase to form an emulsion W (internal aqueous phase) / O (oily phase) / W (external aqueous phase), followed by evaporation of the solvent in the oily phase to Prepare microcapsules The volume of the external aqueous phase is generally about 1 to 10,000 parts, preferably about 5 to 50,000 parts, more preferably Approximately 10 to 2,000 parts per one part of the oily phase.

The emulsifier and the regulatory agent of the osmotic pressure that can be optionally added to said phase external aqueous and the subsequent procedure for preparation are equal to those established in section (I) (i) above.

(II) Phase separation method

In the case of the preparation of the microcapsules by this method, a coacervation agent is gradually added to the organic solution that comprises the substance physiologically active and biodegradable polymer as established in the method drying in water according to section (I) above, while agitated the precipitate and solidified the microcapsules. The agent of coacervation is used in an amount usually of about 0.01 to 1,000 times, preferably approximately 0.05 to 500 times, most preferably approximately 0.1 to 200 times the volume of the oily phase.

As the coacervation agent, there is no particular limitation to the extent that it is a compound of weight high molecular weight, a mineral oil, a vegetable oil or similar that is miscible with an organic solvent and does not dissolve the biodegradable polymer of the invention therein. Examples Specific are silicone oil, sesame oil, oil soy, corn oil, cottonseed oil, coconut oil, flaxseed oil, mineral oil, n-hexane, n-heptane, etc. These They can be used alone or in combination.

The microcapsules thus prepared are collected, washed with heptane or the like repeatedly to separate the agent of coacervation, etc. other than the physiologically substance active and biodegradable polymer of this invention, followed by drying under reduced pressure. Alternatively, in the same way which was established in the method of drying in water according to the section (I) above, the microcapsules are washed and lyophilized, if It is necessary, followed by heat drying.

(III) Spray drying method

For the preparation of microcapsules by this method, the organic solution or dispersion comprising the physiologically active substance and biodegradable polymer as it was established in the method of drying with water according to section (I) The above is sprayed by means of a nozzle in the chamber for drying a spray dryer in order to evaporate the organic solvent in the droplets atomized in a period of Very short time to prepare the microcapsules. Said nozzle It can be nozzle type with two flows, nozzle type a pressure, in the form of a rotating disk or the like. Whenever if necessary, washing and lyophilization can be performed, optionally followed by heat drying, in the same way as it was established in the method of drying in water according to the section (I).

As an example of the form of preparation Unlike microcapsules, there are microparticles, which can be prepared by subjecting the organic solution or dispersion that comprises the physiologically active substance and the polymer biodegradable, as established in the water drying method according to section (I) above, to an evaporation of the organic solvent and water in it under the control of the degree vacuum, for example, using a rotary evaporator up to dryness, followed by spraying by means of a grinder jet or the like to provide fine particles, that is, microparticles When desired, the microparticles thus obtained they can be additionally subjected to washing and lyophilization, optionally followed by heat drying in the same way as the one established in the method of drying with water according to the section (I) above.

The microcapsules or microparticles above obtained can achieve a favorable release of the substance physiologically active corresponding to the speed of decomposition of the biodegradable polymer used therein.

The sustained release composition obtained as before it can be administered as such or after being formulated in the form of any appropriate form of preparation that use it as the starting material, in which said form of preparation includes an injection or implant for the route intramuscular, subcutaneous or intraorganic, a transmucosal agent to through the nasal cavity, rectum, uterus or similar, an agent oral as a solid preparation (for example, capsules as soft gelatin capsules and hard gelatin capsules, granules or powders) and a liquid preparation (for example, a syrup, emulsion or suspension), etc.

For example, the release composition sustained can be prepared in the form of an injection of sustained release by mixing said composition with water and a dispersant (for example, a surfactant such as Tween 80 and HCO-60, a polysaccharide such as sodium hyaluronate, carboxymethyl cellulose and sodium alginate), a preservative (for example, methylparaben, propylparaben), an isotonic agent (for example, sodium chloride, mannitol, sorbitol, glucose or proline) and similar to prepare an aqueous suspension or dispersing said composition in a vegetable oil (for example, sesame oil or corn oil) or similar to prepare an oily suspension. The aqueous or oily suspension is virtually unstable as a sustained release injection.

The particle size of the composition of sustained release may be within a range capable of pass through a needle for injection, which is usually of about 0.1 to 300 µm, preferably about 0.5 to 150 µm, more preferably about 1 to 100 µm average particle size. The average size of particles can be determined by a procedure conventional by itself using an apparatus to measure the particle size distribution with laser analysis (SALD2000A: manufactured by the company Shimadzu Seisakusho).

In order to produce a preparation sterilized using the sustained release composition obtained with the lactic acid polymer of the present invention as a matrix, the stages or complete phases for the preparation can be sterilized Alternatively, a γ-ray sterilization or the incorporation of an agent antiseptic. In any case, there is no particular limitation  for sterilization

The sustained release composition obtained using the lactic acid polymer of the present invention as a matrix is of low toxicity and can be used as a drug safe for mammals (for example, humans, cows, pigs, dogs, cats, mice, rats or rabbits).

The sustained release composition may be used as an agent for the prevention and treatment of various diseases depending on the substance physiologically active included in it. For example, when the substance physiologically active is a derivative of LH-RH, the Composition can be used as an agent for prevention and treatment of sex hormone dependent diseases, especially sex hormone dependent cancers (for example, prostate cancer, uterine cancer, breast cancer, pituitary tumor), benign prostatic hyperplasia, endometriosis, fibroid, precocious puberty, dysmenorrhea, amenorrhea, syndrome premenstrual, multiocular ovarian syndrome, etc., or as a contraception agent (or, in the case of using the effect bounce after administration interruption, for prevention and treatment of infertility). The composition It can also be used as an agent for prevention and treatment of a benign or malignant tumor that is not dependent on sex hormones, but sensitive to LH-RH.

The dosage amount of the composition of Sustained release may correspond to the effective dose of the physiologically active substance as the active ingredient in the same, although it can be varied with the type and content of the physiologically active substance, the formulation, the duration to release the physiologically active substance, the symptom of the disease, animal species, etc. A dosage amount only of the physiologically active substance can be appropriately chosen from an interval of approximately 0.01 at 10 mg / kg body weight, preferably approximately 0.05 to 5 mg / kg body weight for a human adult when the Sustained release preparation is the one that covers 6 months.

A single dosage of the composition of sustained release can be appropriately selected from a range of about 0.05 to 50 mg / kg body weight, more preferably a range of about 0.1 to 30 mg / kg of body weight for a human adult.

The frequency of administration can be properly selected from once for several weeks, a once a month, once for several months (for example, 3 months, 4 months, 6 months), etc., taking into account the type and content of the physiologically active substance as an active ingredient, the formulation, the duration to release the substance physiologically active, the symptom of the disease, the species of the animal, etc.

As indicated above, the polymer of Lactic acid of the present invention is useful as a matrix for sustained release preparations containing a substance physiologically active and completely prevent release excessive initial and retain a stable release rate of the  physiologically active substance for a period of time long, for example, six months or more.

The present invention will be explained below. in detail by way of examples, but these examples should not interpreted to limit the scope of the present invention.

Examples

In the following descriptions, the weight molecular weight average and polymer content are respectively the one in terms of polystyrene measured by gel permeation chromatography (GPC) using polystyrene monodispersed as certified and calculated reference material from it. All measurements were made through a high performance CPG apparatus (manufactured by Tosoh Corp .; HLC-8120GPC) using SuperH4000X2 and SuperH2000 (both manufactured by the company Tosoh Corp.) as the column and tetrahydrofuran at a flow rate of 0.6 ml / min as the mobile phase. The Detection was performed with the differential refractive index.

Production example one

Synthesis of molecular weight lactic acid polymer high

To dehydrated xylene (230 ml), 1.0 was added mol / l of diethyl zinc hexane solution (4.1 ml), tert-butyl acetate (1.35 g) and DL-lactide (230 g), and the polymerization from 120 to 130 ° C for approximately 2 hours. After completion of the polymerization, dichloromethane (120 ml) in the reaction mixture, followed by the addition of acid trifluoroacetic acid (230 ml) thereto to protect the reaction. After completion of the reaction, dichloromethane (300 ml) was added to the reaction mixture, which was then poured into isopropyl ether (2800 ml) to precipitate lactic acid polymers by weight high molecular The precipitate as the target product is subjected to new precipitation repeatedly with dichloromethane / isopropyl ether to provide an acid polymer lactic acid with a weight average molecular weight of approximately 40,000

Reference one

The polymer obtained in the Production Example 1 was dissolved in dichloromethane (600 ml). The resulting solution is washed with water to make it neutral, and a solution was added 90% aqueous lactic acid (70 g), followed by reaction at 40 ° C. When the weight average molecular weight of the polymer dissolved in the reaction mixture reached approximately 20,000, cooling it was made at room temperature and dichloromethane (600 ml) to end the reaction. The reaction mixture was washed with water to make it neutral, concentrated and dried to provide a lactic acid polymer. The content of carboxyl groups terminals in the lactic acid polymer was approximately 80 µmoles relative to 1 g of the polymer, and the content with a weight average molecular weight of no more than 5,000 was 7.29% in weight.

Example one

The polymer obtained in the Production Example 1 was dissolved in dichloromethane (600 ml) and the resulting solution washed with water to make it neutral and aqueous solution was added 90% lactic acid (70 g) followed by reaction at 40 ° C. When the weight average molecular weight of the polymer dissolved in the mixture reaction reached approximately 20,000, cooling was done at room temperature and dichloromethane (600 ml) was added to End the reaction The reaction mixture was washed with water to make it neutral and was added dropwise to isopropyl ether (2800 ml) to precipitate the target lactic acid polymer. He precipitate was collected by decantation and dissolved in dichloromethane (600 ml). The resulting solution was concentrated and dried to provide a lactic acid polymer (160 g). He content of carboxy terminal groups in the acid polymer lactic acid was about 70 µm relative to 1 g of polymer. The weight average molecular weight of the acid polymer high molecular weight lactic acid used, the average molecular weight weight of the lactic acid polymer after hydrolysis and weight average molecular weight of the weight fractions Molecules of the target lactic acid polymer obtained are shown in Table 1.

Examples 2 a 6

In the same manner as in Example 1, prepared the lactic acid polymer of the invention. the weight Weight average molecular weight polymer lactic acid High molecular weight used, the weight average molecular weight of lactic acid polymer after hydrolysis and weight molecular weight average and molecular weight fractions of Target lactic acid polymer obtained are shown in the Table one.

TABLE 1

Ex. one Ex 2 Ex 3 Ex 4 Ex. 5 Ex 6 PM of molecular weight lactic acid polymer high used 40500 43600 40400 43300 38600 55000 Polymer PM of lactic acid after hydrolysis 22200 22000 22700 22200 18600 27200 Polymer PM of lactic acid obtained 22900 22000 21900 22300 19400 28200 Molecular Weight Fraction (%) 1-1000 0.03 0.07 0.00 0.01 0.08 0.04 1-3000 0.95 1.12 0.87 0.90 1.45 0.62 1-5000 3.85 4.17 3.89 3.92 4.89 2.50

From Table 1, it is understood that the lactic acid polymers obtained according to the procedure of the present invention comprise no more than about 5% by weight of the polymer having a weight average molecular weight of no more of about 5000, not more than about 1.5% by weight of polymer having a weight average molecular weight of no more than 3,000 and no more than about 0.1% by weight polymer that It has a weight average molecular weight of no more than 1,000.

Industrial use

The lactic acid polymer of this invention which comprises no more than about 5% by weight of the polymer that It has a weight average molecular weight of no more than 5,000 is useful as a matrix for drug preparations mainly of sustained release The preparation of release microcapsules sustained that encapsulate in them a substance physiologically active produced by using a polymer of lactic acid can completely prevent the initial release excessive physiologically active substance since microcapsules and effectively maintain a release rate stable over a long period of time.

Claims (24)

1. A process for producing a polymer of lactic acid having a weight average molecular weight of 15,000 to 50,000, in which the content of polymeric materials that have a weight average molecular weight of no more than about 5,000 is of not more than 5% by weight, which comprises hydrolyzing a polymer of high molecular weight lactic acid, contact the resulting solution containing the hydrolyzed product with a solvent selected from the group consisting of alcohols, acyclic ethers and aliphatic hydrocarbons and separate and collect the precipitated lactic acid polymer. 2. The method according to claim 1, in which solvent is selected from the group consisting of methanol, ethanol, isopropyl ether and hexane. 3. The method according to claim 1, in which the solvent is isopropyl ether. 4. The method according to claim 1, in which the high molecular weight lactic acid polymer is dissolved in a solvent selected from the group consisting in halogenated hydrocarbons and aromatic hydrocarbons and It is then hydrolyzed. 5. The method according to claim 4, in which solvent is selected from the group that sewed on chloroform, dichloromethane, toluene, o-xylene, m-xylene and p-xylene. 6. The procedure according to any of the claims 1 to 5, wherein the lactic acid polymer of High molecular weight has a weight average molecular weight of 15,000 to 500,000. 7. The procedure according to any of the claims 1 to 5, wherein the lactic acid polymer of High molecular weight has a weight average molecular weight of 30,000 to 100,000. 8. The procedure according to any of the claims 1 to 7, wherein the lactic acid polymer of High molecular weight is that obtained by polymerization in solution. 9. The procedure according to any of the claims 1 to 8, wherein the lactic acid polymer produced has a weight average molecular weight of 15,000 to 30,000 10. The procedure according to any of the claims 1 to 8, wherein the lactic acid polymer produced has a weight average molecular weight of 20,000 a 25,000 11. The method according to claim 1, in which the resulting solution containing the product Hydrolyzate is a solution of the hydrolyzed product of a polymer of lactic acid having a weight average molecular weight of 15,000 to 50,000 after hydrolysis of the acid polymer high molecular weight lactic acid in a selected solvent among the group consisting of halogenated hydrocarbons and aromatic hydrocarbons and the concentration of hydrolyzed product in the solution it is 10 to 50% by weight. 12. The method according to claim 1, in which the state capable of precipitating the acid polymer Lactic goal is to contact the solution that contains the hydrolyzed product with a solvent selected from the group consisting of alcohols, acyclic ethers and hydrocarbons aliphatic, and separate and collect the lactic acid polymer precipitate. 13. The method according to claim 12, in which the solvent is selected from the group consisting in methanol, ethanol, isopropyl ether and hexane. 14. The method according to claim 12, wherein the solvent is isopropyl ether. 15. The method according to claim 12, wherein the high molecular weight lactic acid polymer is dissolved in a solvent selected from the group consisting in halogenated hydrocarbons and aromatic hydrocarbons and It is then hydrolyzed. 16. The method according to claim 15, in which the solvent is selected from the group consisting in chloroform, dichloromethane, toluene, o-xylene, m-xylene and p-xylene. 17. The procedure according to any of the claims 12 to 16, wherein the lactic acid polymer of High molecular weight is that obtained by polymerization in solution. 18. A lactic acid polymer with a weight molecular weight average of 15,000 to 50,000, in which the content of polymeric materials having a weight average molecular weight of no more than 5,000 is no more than 5% by weight.

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19. The lactic acid polymer according to claim 18, wherein the content of polymeric materials which have a weight average molecular weight of no more than 3,000 is of no more than 1.5% by weight. 20. The lactic acid polymer according to claim 17, wherein the content of polymeric materials which have a weight average molecular weight of no more than 1,000 is of no more than 0.1% by weight. 21. The lactic acid polymer according to any of claims 18 to 20, whose weight average molecular weight It is 15,000 to 30,000. 22. The lactic acid polymer according to any of claims 18 to 20, whose weight average molecular weight It's 20,000 to 25,000. 23. A matrix for release preparations sustained, comprising the lactic acid polymer according to any of claims 18 to 22. 24. Use of lactic acid polymer according to any of claims 18 to 22, as a matrix for sustained release preparations.